Abstract While mAb therapies have proven to be potent, controllable and effective treatment modalities for several cancers and leukemias, marketed therapeutic anti-cancer mAb recognize extracellular or cell surface proteins, which constitute only a small fraction of the cellular proteins and are not generally tumor specific. In contrast, mutated or oncogenic tumor associated proteins are typically nuclear or cytoplasmic. These intracellular proteins are usually un-druggable if they are not enzymes or receptors. Intracellular proteins are degraded in the proteasome, processed and presented on the cell surface by MHC class I molecules as T cell epitopes that are recognized by T cell receptors (TCR?s). We choose here to co-opt lessons from the immune system, which has evolved the highly efficient and truly selective T cell with its TCR capable of recognizing HPV viral proteins and phosphorylated intracellular proteins. TCR mimic (TCRm) mAb recognize peptide antigens of these key intracellular proteins in the context of MHC on the cell surface, marry the best features of both the T cell and a mAb and greatly extend the potential repertoire of tumor targets addressable by potent mAb. The Specific Aims are: 1.) To identify and understand optimal cancer-specific targets for TCRm and create TCRm to them. A. Cancer-specific HPV viral oncogenic proteins. B. Upregulated phosphopeptides in cancer cells. We ask: What are the best epitope targets to approach with TCRm from a biological, biochemical, biophysical, or immunological point of view? (EG, certain positions in the sequence or certain amino acids?) Are certain classes of oncogenic proteins or biochemical structures of peptides acceptable? How do we design better screens to discover more selective TCRm? 2.) To understand the regulation of presentation of cancer-specific epitopes in HLA on the cell surface and to characterize the changes in the unique HLA ligandome and its potential effect on immunotherapy. For example, can we modulate the expression of the epitopes or the antigen presentation machinery to our advantage? This may be of particular relevance to the phosphorylated peptides introduced in Aim 1B.? And equally important, how is the MHC ligandome generally affected by these drugs? The manipulation of the ligandome may afford a vast array of new targets for TCRm, T cell therapy and immune checkpoint blockade. 3.) To develop proteomic and genetic tools to help guide us to picking epitopes and predicting which may be safe? Cross-reactivities of the TCR based agents to off-target tissues have resulted in serious, sometimes fatal, adverse events. As one solution, we are developing the PresentER minigene-based system, which relies on a pool of genetically encoded MHC-I ligands individually expressed and presented in mammalian cells. We will apply PresentER to the TCRm we develop. 4.) To contrast and compare therapeutic TCRm platforms for optimal efficacy. We will conduct animal model therapy trials in anticipation of picking the best platform (eg, IgG vs BiTE vs CAR) for advancing these TCRm agents into human trials in the future.